Bioabsorbable polymeric composition for a medical device

ABSTRACT

A biodegradable and biocompatible nontoxic polymeric composition is provided which includes a base material such as a crystallizable polymer, copolymer, or terpolymer, and a copolymer or terpolymer additive. Medical devices manufactured from the composition are also provided.

FIELD OF INVENTION

Disclosed in the embodiments herein is a novel polymer composition,which includes a base material including a one or more bioabsorbablepolymer, copolymer, or terpolymer, with a polymer or copolymer orterpolymer additive. In particular, the novel composition when used tofabricate implants allows for a “soft” breakdown mechanism allowing forthe breakdown of the component polymers to be less injurious to thesurrounding tissue.

BACKGROUND OF INVENTION

A persistent problem associated with the use of metallic stenting isfound in the formation of scar tissue coating of the vascularly locatedstent, the so-called process of restenosis. Moreover, metallic orpolymeric non-absorbable stents may prevent vascular lumen remodelingand expansion. Numerous approaches have been tried to prevent or healtissue injury and reduce complement activation of the immune response.Furthermore, there is a need for a reduced inflammatory response andlower potential for trauma upon break-up of an implant and/or itscomponent materials. A desirable improvement target may be found in theneed for increased flexibility of shape and structure of medical devicesfor implantation, particularly into blood vessels.

Among the many commercially available bioabsorbable polymers arepoly-alpha-esters (e.g., lactides (i.e., L-lactide and D,L-lactide)) andglycolides, polyester ethers (i.e. polydioxanone), and polycarbonates(i.e., glycolide or lactide-co-trimethylene carbonate), and tyrosinebased polycarbonates. Many other bioabsorbable polymers are beingdeveloped for commercial use, particularly in different modes of drugdelivery, which polymeric substances include polyethyleneglycol-co-lactides, polyanhydides, polyorthoesters, polyester-amides orcyanoacrylates.

The present inventors have recognized a need to develop a compatiblepolymer blend for implants, such as stents and vascular syntheticgrafts, which provide a toughening mechanism to the base polymer whenthe medical device is deployed in the body. They have hypothesized thatthe later may be performed by imparting additional molecular free volumeto the base polymer to encourage sufficient molecular motion to allowfor re-crystallization to occur at physiological conditions especiallywhen additional molecular strain is imparted to the implant. They havetheorized that increased molecular free volume can also increase therate of water uptake adding both a plasticizing effect as well asincreasing the bulk degradation kinetics.

REFERENCES

Reference is made to U.S. Pat. No. 6,607,548 B2 (Inion Ltd), issued Aug.19, 2003, which discloses compositions are biocompatible andbioresorbable using a lactic acid or glycolic acid based polymer orcopolymer blended with one or more copolymer additives. Implants madeaccording to the '548 disclosure are said to be cold-bendable withoutcrazing or cracking. Reference is also made to EP 0401844 whichdiscloses a blend of poly-L-lactide with poly L-DL-lactide. Reference isalso made to U.S. Pat. No. 5,317,064 disclosing polylactidestereocomplexing compositions.

SUMMARY

A novel polymer composition is provided that allows for a “soft”breakdown in vivo such that the breakdown proceeds while being friendlyto the surrounding tissue (e.g., less inflammatory response, andrendering lower potential for trauma upon break-up of an implant). Thepolymer composition, includes a base material such as a bioabsorbablepolymer, copolymer, or terpolymer, which are selected for their abilityto undergo hydrolytic and/or enzymatic degradation and absorption invivo, and a copolymer or terpolymer additive.

Such novel polymer composition may comprise a polymer blend with theblend being optimized for enhanced hydrophilic property in order toreduce complement activation and minimize or prevent opsonization (seeDong and Feng, J of Biomedical Materials Research part A DOI 10.1002,2006). To improve hydrophilicity, the novel polymer composition may beformulated to provide increased molecular free volume, allowing forincreased uptake of water, and the rate of uptake of water, adding botha plasticizing effect as well as increasing the bulk degradationkinetics. Additional molecular free volume may also be used to encouragesufficient molecular motion so as to allow for re-crystallization tooccur at physiological conditions, in particular when strain on thecomposition leads to additional molecular strain.

In an embodiment, there is provided a polymer/polymer blend implantcomprising a biodegradable scaffold displaying flexibility for crimpedfastening on a carrier system, as well as displaying elastic strutstrength upon implantation into the body due to induction ofcrystallization if the polymer/polymer blend. The implant may comprise,for example, a tube-shaped expandable scaffold configured to fit withinan organ space, such as the vasculature, including the cardiovasculatorysystem. Such a scaffold may achieve a combination of mechanicalproperties balancing elasticity, rigidity and flexibility.

In one embodiment the polymer composition and/or formulation, contains apolymer such as a poly (L-lactide), and/or a poly (D-lactide) as thebase polymer, or copolymers thereof. In respect of copolymercompositions, the copolymers may be synthesized as block copolymers oras “blocky” random copolymers. The lactide chain length of copolymersmay be selected to be sufficiently long enough to crystallize. Shorteneddegradation time, to provide, for example, enhanced degradation kineticsmay be obtained by using a lower molecular weight composition and/or abase polymer that is more hydrophilic or suspect to hydrolytic chainscission.

Optionally included in such embodiment composition is modifyingcopolymers including, for example, poly L(orD)-lactide-co-tri-methylene-carbonate, or poly L(orD)-lactide-co-ε-caprolactone, which may be admixed to link the basepolymers. In such copolymer-modifying copolymer embodiment, thecomposition may allow the development of a crystal morphology that canenhance the mechanical properties of the medical device, enhanceprocessing conditions, and provide potential of cross-moietycrystallization, for example, strain induced thermal cross-links. Themodifying polymer or co-polymer may also be used to affect enhanceddegradation kinetics, such as with an ε-caprolactone copolymer moietywhere the caprolactone remains amorphous with resulting segments moresusceptible to hydrolysis.

In another embodiment composition the base copolymer includes L-lactideD-lactide wherein one chain moiety is sufficiently long enough, and notsterically hindered, to crystallize with another lactide moiety.Optional co-monomers with the base co-polymer include lesser sizedmoieties such as, for example, glycolide, polyethylene glycol (PEG), ormonomethoxy-terminated PEG (PEG-MME).

In another embodiment, one may incorporate PEG copolymers, for exampleeither AB di-block or ABA tri-block with the PEG moiety beingapproximately 1%, may be employed with maintenance of the mechanicalproperties of the lactide (see Enderlie and Buchholz SFB May 2006).Incorporation of either PEG or PEG-MME copolymers may also be used tofacilitate drug attachment to the polymer, for example, in conjunctionwith a drug eluting medical device.

Embodiment hydrophilic compositions of the present, invention areintended to allow for a “soft” or very gradual breakdown mechanism suchthat the breakdown proceeds while being friendly to the surroundingtissue (less inflammatory response, and rendering lower potential fortrauma upon break up of an implant). Selecting a polymer or copolymerhaving an enhanced hydrophilic property for either the base polymer, orthe additive, or both, the polymer blend may reduce complementactivation and minimize or prevent opsonization.

In an embodiment composition, the polymers are selected to provide aracemate or stereocomplex crystal structure. For example, the copolymersmay comprise a D-lactide and L-lactide, in a ratio sufficient to form aracemic crystal structure. A scaffold produced of such polymercompositions may provide enhanced mechanical properties through amolecular reorientation and crystallization effected during the radialstrain of expansion from a crimped state to an expanded or implantedstate. More specifically, a tubular stent scaffold of such embodimentmay undergo racemate crystallization at the more tightly angledmeandering struts after being crimped on to a carrier/implanting device,while still maintaining a substantially amorphous matrix elsewhere. Whena tubular stent scaffold includes a hoop structure, the polymer may befabricated so as to be capable of crystallization in the orthogonallyexpansion stretched ring or hoop structures during implantationgenerating strong resistance against collapse.

In another embodiment, cross-moiety crystallization is promoted betweena base polyer, e.g., poly L-lactide or poly D-lactide, and a modifyingcopolymer with the same lactide segment, e.g., LPLA-TMC or DPLA-TMCrespectively.

The composition of the polymer embodiments also may be modified for theparticular functions assigned to a medical device. Thus, the polymer maycontain fillers in the form of drugs or other pharmaceutical agents suchas small molecule inhibitors of endogenous enzymes, radio-opaque markers(powders or other suitable particulates, and ether factors.

The compositions of the present invention may include pharmacologicalagents such as tacrolimus, sirolimus, everolimus, prostacyclin,prostacyclin analogs, α-CGRP, α-CGRP analogs or α-CGRP receptoragonists; prazosin; monocyte chemoattactant protein-1(MCP-1);immunosuppressant drugs such as rapamycin, drugs which inhibit smoothmuscle cell migration and/or proliferation, antithrombotic drugs such asthrombin inhibitors, immunomodulators such as platelet factor 4 andCXC-chemokine; inhibitors of the CX3CR1 receptor family;antiinflammatory drugs, steroids such as dihydroepiandrosterone (OHEA),testosterone, estrogens such as 17β-estradiol; statins such assimvastatin and fluvastatin; PPAR-alpha ligands such as fenofibrate andother lipid-lowering drugs, PPAR-delta and PPAR-gamma agonists such asrosiglitazone; PPAR-dual-αγ agonists, LBM-642, nuclear factors such asNF-κβ, collagen synthesis inhibitors, vasodilators such asacetylcholine, adenosine, 5-hydroxytryptamine or serotonin, substance P,adrenomedulin, growth factors which induce endothelial cell growth anddifferentiation such as basic fibroblast growth factor (bFGF),platelet-derived growth factor (PDGF), endothelial cell growth factor(EGF), vascular endothelial cell growth factor (VEGF); protein tyrosinekinase inhibitors such as Midostaurin and imatinib or anyanti-angiogenesis inhibitor compound; peptides or antibodies whichinhibit mature leukocyte adhesion, antibiotics/antimicrobials, and othersubstances such as tachykinins, neurokinins or sialokinins, tachykininNK receptor agonists; PDGF receptor inhibitors such as MLN-518 andderivatives thereof, butyric acid and butyric acid derivatives puerarin,fibronectin, erythropoietin, darbepotin, serine proteinase-1 (SERP-I)and the like.

Included in embodiments of the present invention are devices made fromsuch polymer compositions. Such devices include medical devices forimplantation into a patient such as, without limitation, biodegradable,stents, stent grafts, vascular synthetic grafts, orthopedic devices,nerve guides, maxillofacial cranial devices, catheters, vascular shunts,or valves. Such devices may display bioabsorbable properties. Suchimplantation devices may include structure useful for inserting theimplant into the body. For example, such implants may include snap-fitstructure allowing for interaction between suitable parts of the medicaldevice to allow the device to be held in a reduced size state which mayaid in its insertion, and may aid its interaction with a carrier deviceused for its insertion (e.g., securing it on a carrier device withoutcreep).

Embodiments of the invention are also directed to methods of making thebiodegradable polymer compositions and methods for making the medicaldevices from the polymer compositions disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts change in modulus with recrystallization of LPLA/LPLA/TMCnon-racemate blend versus a DPLA/LPA/TMC with only cross moiety racemateand a DPLA/LPLA/LPLA-TMC with additional racemate formation;

FIG. 2A and FIG. 2B depict DSC curves of polymer with racemate andwithout racemate formation, respectively: as illustrated racemate meltis shown to be significantly different in pro file for the +racemate vs.the −racemate.

FIGS. 3A-3G illustrate an embodiment method of radiopaque depot markingof a stent medical device: as seen in (a)-(d), radiopaque material maybe extruded into a cavity housed in the structure (g). As seen incut-off views (e) and (f), such cavity may be a through-hole.

FIGS. 4A-4C illustrates different stent patterns of a scaffold withradiopague markers. As illustrated, the radiopaque markers can be placedat different locations on the stent patterns, while still allowingdetection using radiopaque detection means.

FIG. 5A and FIG. 5B illustrate a planar view of a stent material withradiopaque markers. As illustrated in FIGS. 5A and 5B, the radiopaquemarkers can be aligned in the structure to allow for easieridentification upon imaging or use of other detection methods.

FIG. 6 shows an overview perspective of an actual stent with anembodiment radiopaque marker pattern, each located at a connectionjunction of the meandering strut.

FIG. 7 shows a close-up view of a portion of the radiopaque marked stentof FIG. 6.

FIG. 8 shows in perspective view a stent embodiment of the presentinvention deployed on a balloon catheter.

FIG. 9 depicts a fully expanded bioabsorbable scaffold stent comprisingring structuring showing fully crystallized holding rings or hoops.

FIG. 10A and FIG. 10B illustrates DSC flow curves demonstrating singleTg and 10B shows a DSC flow curve showing double Tg.

DETAILED DESCRIPTION

In embodiments herein there are illustrated various compositions forbioabsorbable polymer blends, methods for making the compositions, andmedical devices made of such bioabsorbable polymer blends.

The following nomenclature will now be used with the polymernomenclature being based on the presence of the monomer type,

-   -   LPLA: Poly(L-lactide)    -   LPLA-PEG: Poly(poly-L-lactide-polyethylene glycol)    -   DPLA: Poly(D-lactide)    -   DPLA-TMC: Poly(poly D-lactide-co-trimethylene carbonate)    -   DLPLA: Poly(DL-lactide), a racemic copolymer D-co-L-lactide    -   LDPLA: Poly(L-co-D-lactide)    -   LDLPLA: Poly(L-co-DL-lactide), named for the method of monomer        introduction    -   PGA: Poly(glycolide)    -   PDO: Poly(dioxanone) (PDS is Trademark)    -   SR: “Self reinforced” (a processing technique)    -   TMC: Trimethylene carbonate    -   PCL: Poly(ε-caprolactone)    -   LPLA-TMC: Poly(poly L-lactide-co-trimethylene carbonate)    -   LPLG: Poly(L-lactide-co-glycolide)    -   POE: Poly Orthoester

In an embodiment of the present invention, the composition comprises abase polymer of poly(L-lactide) or poly(D-lactide). Advantageous basepolymer compositions include blends of poly(L-lactide) andpoly(D-lactide). Other advantageous base polymer compositions includepoly(L-lactide-co-D-L-lactide) or poly(D-lactide-co-D,L-lactide) with aD,L-lactide co-monomer molar ratio from 10 to 30%, andpoly(L-lactide-co-glycolide) or poly(D-lactide-co-glycolide) with aglycolide co-monomer molar ratio from 10 to 20%.

Another embodiment embodies a base polymer featuring a poly (L-lactide)moiety, and/or a poly (D-lactide) moiety, linked with a modifyingcopolymer thereof, including poly (L-lactide-co-tri-methylene-carbonateor poly(D-lactide-co-tri-methylene-carbonate) and(L-lactide-co-ε-caprolactone), or poly(D-lactide-co-ε-caprolactone), inthe form of block copolymers or blocky random copolymers, wherein thelactide chain length is sufficient to affect cross-moietycrystallization.

In another embodiment, the polymer composition allows the development ofthe lactide racemate (stereo complex) crystal structure, between the Land D moieties, to further enhance the mechanical properties of thebioabsorbable polymer medical device. The formation of the racemate(stereo complex) crystal structure can accrue from formulations such ascombinations of:

-   -   Poly L-lactide with Poly D-lactide with Poly L-lactide-co-TMC;    -   Poly D-lactide with Poly L-lactide-co-TMC;    -   Poly L-lactide with Poly D-lactide-co-TMC;    -   Poly L-lactide with Poly D-lactide with Poly D-lactide-co-TMC;    -   Poly L-lactide-co-PEG with Poly D-lactide-co-TMC; and    -   Poly D-lactide-co-PEG with Poly L-lactide-co-TMC.        Poly-lactide racemate compositions of this embodiment may have        an especially advantageous characteristic in being “cold        formable or bendable” without adding heat. Cold-bendable        scaffolds of the invention do not require heating to become        flexible enough to be crimped onto a carrier device or        accommodate irregularly shaped organ spaces. Cold bendable        ambient temperatures are defined as room temperature not        exceeding 30° C. Cold-bendable scaffolds, for example, afford        sufficient flexibility when implanted allowing for an expanded        scaffold device in an organ space such as pulsating vascular        lumen. For example, in terms of a stent, it may be desirable to        utilize polymeric compositions that afford mostly amorphous        polymer moieties after fabrication that can crystallize        particularly when the secondary nested or end-positioned        meandering struts when the scaffold is strained by stretching        upon balloon expansion for implantation. Such cold-bendable        polymeric scaffold embodiments of are not brittle and do not        have to be preheated to a flexible state prior to implantation        onto a contoured surface space in the body. Cold-bendability        allows these blends to be crimped at room temperature without        crazing, and moreover, the blends can be expanded at        physiological conditions without crazing.

Poly-lactide racemate compositions and non-racemate compositions ofembodiments herein may be processed to have blocky moieties allowingcross moiety crystallization even with the addition of an impactmodifier to the blend composition. Such a blend introduces thepossibility to design device specific polymer compositions or blends byproducing either single or double Tg's (glass melt transition points).

Poly-lactide racemate compositions may show significant improvement inre-crystallization capability over, for example, non-racematePLDL-lactide blends. An advantageous racemate alignment of the differentpolylactide moieties can be achieved, for example, by blending apoly-D-lactide with the copolymer poly L-lactide-co-TMC capable offorming racemate crystal across the different polylactidestereomoieties, for example, without limitation, when stretched duringexpansion to the required emplacement diameter. This strain inducedcrystallization, without adverse crazing, results in an increase of themechanical properties reflected also in a positive change of modulusdata over the base of the base materials.

Cross moiety crystallization of compositions with copolymers appears tobe limited to copolymer with monomer molar ratios ranging from about90:10 through 50:50. In fact, at a molar ratio of 50:50, the polymermoieties sterically impeded crystallization whereas the greater ratiosare much more suitable for cross moiety crystallization. On the basis ofexperimental induced crystallization, different blends with variousconcentrations of lactide copolymers such as TMC or εCL, to which anexcess of poly (D-lactide) for racemate alignment with the L-lactidecomponent has been added, the effective concentration of the copolymerin a racemate composition may be equal to, or less than, 40%. Thus, thethermal cross-links formed by cross moiety crystallization serves toreduce elongation or creep while maintaining the intended tougheningmechanism. The advantageously strong racemate composition affordsincreased modulus data in tensile tests avoiding the method for reducingthe tensile strength in the polymer blend.

An advantageous racemate composition embodiment provides a bioabsorbablepolymer with minimal degradation in terms of high residual monomer levelsuch that the contaminant monomeric residual fraction does not exceedabout 0.5%, or preferably not in excess of about 0.3%. In embodimentconcentration of monomeric contaminant of the polymer of the presentinvention is as low as about 0.2%.

Polymer compositions of embodiments described herein may comprise a basepolymer present from about 70% to 95% by weight, or from about 70% to80% by weight of the composition. For example, in one embodiment, thepolymer formulation may comprise from about 70% by weight poly L-lactide(about 2.5 to 3 IV) with the poly L-lactide-co-TMC (70/30 mole/mole)(1.4 to 1.6 IV). In another embodiment, the polymer formulation maycomprise 70% by weight bib lock poly L-lactide-co-PEG(99/01 mole/mole)(2.5 to 3 IV) with the poly L-lactide-co-TMC(70/30 mole/mole) (1.4 to1.6 IV). Furthermore, the polymer composition may comprise a formulationof about 70% by weight diblock poly L-lactide-co-PEG-MME(95/05mole/mole) (2.5 to 3 IV) with poly L-lactide-co-TMC(70/30 mole/mole)(1.4 to 1.6 IV). Other embodiments provide formulations whereinε-caprolactone is substituted in a composition for the aforementionedTMC. Similarly, an embodiment may provide formulations wherein PEG-MMEmay be substituted for PEG.

As is understood in this art, polymer compositions of the presentinvention can be customized to accommodate various requirements of theselected medical device. The requirements include mechanical strength,elasticity, flexibility, resilience, and rate of degradation underphysiological and localized anatomical conditions. Additional effects ofa specific composition concern solubility of metabolites, hydrophilicityand uptake of water and any release rates of matrix attached or enclosedpharmaceuticals.

The polymer implant utility can be evaluated by measuring mass loss,decrease in molecular weight, retention of mechanical properties, and/ortissue reaction. More critical for scaffold performance axe hydrolyticstability, thermal transitions crystallinity and orientation. Otherdeterminants negatively affecting scaffold performance include, but notexclusively, monomeric impurities, cyclic and acyclic oligomers,structural defects and aging.

The medical device fashioned from the polymer compositions above may besignificantly amorphous post extrusion or molding. Such devices may besubjected to controlled re-crystallization to induce incremental amountsof crystallinity and mechanical strength enhancement. Furthercrystallization can be induced by strain introduction at the time ofdevice deployment. Such incremental re-crystallization may be employedeither on a device “blank” prior to secondary or final fabrication (suchas by laser cutting) or post such secondary fabrication. Crystallization(and thus mechanical properties) can also be maximized by straininduction such as by “cold” drawing polymeric tubing, hollow fiber,sheet or film, or monofilament prior to further fabrication.Crystallinity has been observed to contribute a greater stiffness in themedical device. Therefore, the polymer composition and steric complex ofthe scaffold has both amorphous and paracrystalline moieties. Theinitially semicrystalline polymer portion can be manipulated by theaction of stretching or expansion of a given device. Yet an adequateamount of amorphous polymeric character is desirable for flexibility andelasticity of the polymeric device. The usual monomer components includelactide, glycolide, caprolactone, dioxanone, and trimethylene carbonate.

In one embodiment, the medical device manufactured from such compositionis a scaffold strut structure for implantation into the body, forexample, a stent. These structures are to be crimpable so as to betightened around and thereby fastened on a carrier device. Conversely,the same scaffold is expandable without stress crazing or cracking. Themechanical properties of a stent biodegradable scaffold implant requiresstrength, elasticity and flexibility to cope with the fluctuating pulsecompression of the surrounding tissue without dislocation and injuriousimpact at the implantation site throughout the desirable gradual processof biological degradation and absorption of the scaffold struts.Therefore, these properties have to be build into the scaffold polymercontent and structure in terms of certain criteria. The stent shouldhave polymeric properties are amenable to expansion by means of athermally enhanced or non-thermal balloon. The polymeric embodimentprovides the ability to orient and/or crystallize in scaffold strutsupon orthogonal strain of deployment, by e.g. balloon dilation. Thus,the crystallization effect provides improved mechanical properties suchas hoop strength, as in compression resistance, elastic recoil, andpolymer stability. The stent may also be constructed to allow relativelyuniform exposure to local tissue or circulatory bioactive factors andenzymes perfusing and acting on the polymer structure duringbioabsorption.

Advantageously, the rate of in situ breakdown kinetics of the polymericmatrix of an organ space implant, such as a cardiovascular stent, issufficiently gradual to avoid tissue overload, inflammatory reactions orother more adverse consequences. In an embodiment, the scaffold isfabricated to survive at least one month.

As shown in the following examples, the comparative degree of amorphousand crystalline properties can be designed into the polymer. Thus,L-lactic polymers are found to yield a semicrystalline morphology, whilethe racemic poly(D,L-lactic) results in an amorphous polymer. Apoly(L-glycolide) is semicrystalline. The following examples show aprocess for fabricating bioabsorbable scaffold PLDL-lactide blends.

Example 1

A test disk was injection molded from a composition of a racemic mixtureof poly(L-lactide) and poly(D-lactide) with 15% by weight copolymermodifier of a 50:50 molar ratio poly(L-lactide-co-TMC). Injectioncylinder temperatures were between 110° C. and 225° C. with a moldtemperature of 50° F. to 82° F., to mold an amorphous disk. Injectionpressure was set between 1300 and 1450 psi with a 50 second cycle time.It was found that an adequate degree of crystallinity could be producedin the polymer. DSC analysis confirmed the formation of both theconventional lactide crystal and the racemate crystal morphology.

Example 2

The polymer mixture is blend extruded into a narrow tube, and a scaffoldform may be cut with a laser under a microscope to produce a cage-likemesh device of meandering struts connected to hoop-like rings positionedat one end and/or at the middle portion of the device. The resultingscaffold device includes a primary meandering scaffold forming acircumferential mesh structure containing a pattern of secondarymeandering struts nested within the scaffold as well as at or near theends of the scaffold. The second meandering struts may be shaped to formupon full implant expansion, a less sinusoidal or more straight hoop orring shape than the first meandering struts, in orthogonal direction tothe longitudinal axis of the tubal device. The expanded secondmeandering struts having smaller or shorter meandering loops or curvesare stretched further during expansion. These struts may form thus hoopsof greater crystallinity and therefore greater rigidity with elasticityso that the implant is resistant against creeping change or dislocation.

Example 3

The polymer compositions may be prepared from commercially availablegranular materials and copolymer additives. The dry components areweighed according to the desired weight ratio into a container rotatingin a suitable for 30 minutes or until a homogenous mixture is obtainedfollowed by further drying in vacuo at 60° C. for 8-12 hours orovernight. As described above, the thoroughly mixed components may bemelt blended and injection molded into a pair of matching plates. Thecomposition rendering polymer sheets exhibiting a suitable elasticityand an appearance of amorphous morphology or very low degree ofcrystallinity under a polarizing light source may be extruded with aback pressure of 40-50 bar under melting temperature of 120-160° C.while being homogenized with a 28 blade screw at 40-80 rpm. The extrudermelt blending and homogenization conditions of the material duringmetering phase of the process may include a screw speed of 60-100 rpm.The relatively mild injection molding process may use an exittemperature of 120° C.-150° C., at a velocity of 80-300 mm/s, a maximuminjection pressure of 2500 bar, a pack pressure of 1000-2300 bar for 3to 8 seconds, into mold kept at room temperature. The total cycle timemay be one minute or less from injection to ejection from the moldplate.

Example 4

Dry polymer racemate mixture of poly(D-lactide) andpoly(L-lactide-co-TMC) was blended at a weight ratio of 70:30 andprocessed with a single melt-extrusion step at 185-225° C. into atube-shaped amorphous bioabsorbable racemate capable polymer blend. Theinstant method of melt-extrusion minimized polymer degradation due toexcessive exposure to heat and shear. Subsequent testing showedeffective induction of crystallization and development of the racematecrystal morphology. Such racemate copolymer hybrids have been found toconfirm effective cross moiety crystallization. Moreover, racematematerial can be created to have multiple transition temperaturesindicating polymorphic and or pleomorphic structures. Thus, it has beenfound that the instant polymer scaffold was sufficiently flexible to becrimped onto a rubber bulb carrier, but for deployment in tissue thepolymer moiety strength may be increased proportionally to expansionstrain.

Example 5

Dry poly (L-lactide) with a racemic excess of poly (D-lactide) wereblended with 30% by weight poly(L-lactide-co-TMC) under dry nitrogen,followed by melt blending and extrusion followed by rapid air quenching.Subsequent re-crystallization and testing confirmed significantly moreracemate formation and increase in modulus over the formulation ofexample 4.

Synthesis is influenced by several distinct factors affecting themechanical performance of the bioabsorbable polymer suitable for animplantable structure, such as monomer selection, initiator selection,polymerization conditions, and presence of additives or residuals.Furthermore, polymeric properties that determine the effectiveness ofthe implant include hydrophilicity, crystallinity, melt and glasstransition temperatures, molecular weight, molecular weightdistribution, end groups, sequence distribution i.e., random vs.blocky), presence of residual monomer or additives, and stability duringconversion.

In one embodiment pharmaceutical compositions may be incorporated withinthe polymers by, for example, grafting to the polymer active sites, orcoating. An embodiment of the polymer according to the invention affordsattachment or incorporation the biological healing factors or otherdrags in the polymeric matrix, or a polymer coating.

In another embodiment, the composition may be constructed tostructurally enclose or attach to drugs in the polymeric matrix. Thepurpose of such additives may to provide, for example with respect to astent, treatment of the cardiovascular system or in vascular site incontact with the medical device polymer. The kind of enclosure orattachment of drugs in the polymer may determine the rate of releaseform the device. For example, the drug or other additive may be bound inthe polymer matrix by various known methods including but not limited tocovalent bonds, non-polar bonds as well as an ester or similarbioreversible bonding means.

Embodiments of the bioabsorbable polymeric scaffold of an implantableconfiguration are known as useful for drug delivery. Therefore asdescribed below, an extensive variety of compounds are possible agentsto treat or modify the affected tissue at tire locus of implantation aswell as possibly further as e.g. in the entire cardiovascular system orother affected organs.

Examples of compounds or pharmaceutical compositions which can beincorporated in the matrix, and/or impregnated into the medical deviceinclude, but are not limited to tacrolimus, sirolimus, everoolimus,prostacyclin, prostacyclin analogs, α-CGRP, α-CGRP analogs or α-CGRPreceptor agonists; prazosin; monocyte chemoattactant protein-1 (MCP-1);immunosuppressant drugs such as rapamycin, drugs which inhibit smoothmuscle cell migration and/or proliferation, antithrombotic drugs such asthrombin inhibitors, immunomodulators such its platelet factor 4 andCXC-chemokine; inhibitors of the CX3CR1 receptor family,antiinflammatory drugs, steroids such as dihydroepiandrosterone (DHEA),testosterone, estrogens such as 17β-estradiol; statins such assimvastatin and fluvastatin; PPAR-alpha ligands such as fenofibrate andother lipid-lowering drugs, PPAR-delta and PPAR-gamma agonists such asrosiglitazone; PPAR-dual-αγ agonists, LBM-642, nuclear factors such, asNF-κβ, collagen synthesis inhibitors, vasodilators such asacetylcholine, adenosine, 5-hydroxytryptamine or serotonin, substance P,adrenomedulin, growth factors which induce endothelial cell growth anddifferentiation such as basic fibroblast growth factor (bFGF),platelet-derived growth factor (PDGF), endothelial cell growth factor(EGF), vascular endothelial cell growth factor (VEGF); protein tyrosinekinase inhibitors such as Midostaurin and imatinib or anyanti-angionesis inhibitor compound; peptides or antibodies which inhibitmature leukocyte adhesion, antibiotics/antimicrobials, and othersubstances such as tachykinins, neurokinins or sialokinins, tachykininNK receptor agonists; PDGF receptor inhibitors such as MLN-518 andderivatives thereof, butyric acid and butyric acid derivatives puerarin,fibronectin, erythropoietin, darbepotin, serine proteinase-1 (SERP-1)and the like. The aforementioned compounds and pharmaceutical substancescan be applied to the scaffold of the device alone or in combinationsand/or mixtures thereof. Moreover, the polymer attached or enclosed drugmaterial can be bound covalently or ionically to the polymeric moietiesas well as entrapped physically in the polymeric matrix. Whereversuitable the drug may be present in the form ester-type cross-links,microparticles, or micelle clusters.

In one embodiment, a bioabsorbable implantable medical device be coveredwith a biodegradable and bioabsorbable coating containing one or morebarrier layers where the polymer matrix contains one or more of theaforementioned pharmaceutical substances. In this embodiment, thebarrier layer may comprise a suitable biodegradable material, includingbut not limited to, suitable biodegradable polymers including:polyesters such as PLA, PGA, PLGA, PPF, PCL, PCC, TMC and any copolymerof these; polycarboxylic acid, polyanhydrides including maleic anhydridepolymers; polyorthoesters; poly-amino acids; polyethylene oxide;polyphosphacenes; polylactic acid, polyglycolic acid and copolymers andmixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L-lactide),poly(lactic acid-coglycolic acid), 50/50 (DL-lactide-co-glycolide);polydioxanone; polypropylene fumarate; polydepsipeptides;polycaprolactone and co-polymers and mixtures thereof such aspoly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate;polyhydroxybutyrate valerate and blends; polycarbonates such astyrosine-derived polycarbonates and arylates, polyiminocarbonates, andpolydimethyltrimethyl-carbonates; cyanoacrylate; calcium phosphates;polyglycosaminoglycans; macromolecules such as polysaccharides(including hyaluronic acid; cellulose, and hydroxypropylmethylcellulose; gelatin; starches; dextrans; alginates and derivativesthereof), proteins and polypeptides; and mixtures and copolymers of anyof the foregoing. The biodegradable polymer may also be a surfaceerodable polymer such as polyhydroxybutyrate and its copolymers,polycaprolactone, polyanhydrides (both crystalline and amorphous),maleic anhydride copolymers, and zinc-calcium phosphate. The number ofbarrier layers that the polymeric scaffold on a device may have dependson the amount of therapeutic need as dictated by the therapy required bythe patient. For example, the longer the treatment, the more therapeuticsubstance required over a period of time, the more barrier layers toprovide the pharmaceutical substance in a timely manner.

In another embodiment, the additive in the polymer composition may be inthe form of a multiple component pharmaceutical composition within thematrix such as containing a fast release pharmaceutical agent to retardearly neointimal hyperplasia/smooth muscle cell migration andproliferation, and a secondary biostable matrix that releases a longacting agent for maintaining vessel patency or a positive blood vesselremodeling agent, such as endothelial nitric oxide synthase (eNOS),nitric oxide donors and derivatives such as aspirin or derivativesthereof, nitric oxide producing hydrogels, PPAR agonist such as PPAR-αligands, tissue plasminogen, activator, statins such as atorvastatin,erythropoietin, darbepotin, serine proteinase-1 (SERP-1) andpravastatin, steroids, and/or antibiotics.

In another embodiment, there is provided a method for treating vasculardisease such as restenosis and atherosclerosis, comprising administeringa pharmaceutical substance locally to a patient in need of suchsubstance. The method comprises implanting into a vessel or hollowedorgan of a patient a medical device of the present invention with acoating, which coating comprises a pharmaceutical composition comprisinga drug or substance for inhibiting or slowing smooth muscle cellmigration and thereby restenosis, and a biocompatible, biodegradable,bioerodable, nontoxic polymer or non-polymer matrix, wherein thepharmaceutical composition comprises a slow or controlled-releaseformulation for the delayed release of the drug. The coating on themedical device can also comprise a ligand such as an antibody forcapturing cells such as endothelial cells and or progenitor cells on theluminal surface of the device so that a functional endothelium isformed.

The medical devices which may be made from the compositions of thepresent disclosure may comprise any medical device for implantationincluding, without limitation, stents, grafts, stent grafts, syntheticvascular grafts, shunts, catheters, and the like. The medical deviceembodiments of the present invention may provide a drug delivery systemthat features different gradual release rates of a drug or a mixture ofdrugs for effective treatment of the implant site in a tissue or organstructure. Such devices may also include in the composition, or in thestructure composed of the composition, radiopaque substances forenhancing traceability of the medical device in situ. Such radiopaquesubstances may include nontoxic materials which would interfere with theintended healing process.

The medical devices of the invention can be structurally configured toprovide the ability to change and conform to the area of implantation toallow for the normal reestablishment of local tissues. The medicaldevices can transition from solid to a “rubbery state” allowing foreasier surgical intervention, than, for example, a stainless steelstent. Moreover, the rubbery state of the device offers less risk of anyinjurious encounters with the vascular walls in the event of a removalfrom a vascular location.

In embodiments disclosed herein, the medical device comprises a stent,which is structurally configured to be deployed into, for example, anartery or a vein, and be able to expand in situ, and conform to theblood vessel lumen, to reestablish blood vessel continuity at the siteof injury. The stent can be configured to have many differentarrangements so that it is crimpable when loading and expandable andflexible at physiological conditions once deployed. Various embodimentsof biodegradable polymeric stents, and/or stent walls with differentconfiguration may be envisioned, as are illustrated in co-pending patentapplications, for example, the stent is a tubular structure comprisingstruts operably designed to allow blood to traverse its walls so thatthe adjacent tissues are bathed or come in contact with it as bloodflows through the area. The particular stent design depends on the sizeof the stent radially and longitudinally.

In respect of stents, the composition of the polymer may be designed toafford a combination of rigidity, elasticity, and flexibility such thatthe in situ effect of the stent results in effective luminal support forhealing and drug treatment of the cardio-vascular system. With respectto stents, in particular, the composition of the polymers may beadjusted and selected such that it affords sufficient polymer strengthto resist fluctuating vascular compression forces and blood flow rates.This structural and flexural strength is designed to persist during insitu bio-erosion of polymeric material which may extend over many days,or a few months. This residual strength of the polymer can be measurablymonitored for at least enough time before a collapse of the treatedvessel and keep the healing process on track. A composition for a stentmay be designed to provide transitions gradually from the initialrigidly buttressing character within a vascular location to arubber-like or “rubbery” consistency capable of maintaining a clinicalfunction, such as preventing restenosis. The polymer composition mayfurther be selected to offer smooth polymerized surfaces both proximaland distal to vascularly engaged regions so as to minimize tissueirritation or injury and thus not to evoke a clinically significantimmune response. The polymer may be selected so as to allow a balloondriven expansion. Such an expandable medical device would comprise athermal balloon or non-thermal balloon wherein the medical device canhave a structure which is crimpable during loading and expandablewithout stress crazing in physiological conditions. Advantageously, thepolymer composition may be selected to orient and/or crystallize uponstrain of deployment, for example during balloon dilation, in order toimprove its mechanical properties.

By careful selection of polymer compositions and structural construct ofthe medical device, immunogenicity and inflammatory responses can beminimalized. For example, if the device is shaped to lack protrudingcontours there may be precluded, or at least minimalized, polymeric andstructural antigenicity so as to slow an immune response. Similarly, byselecting appropriate copolymers in the appropriate ratio, the resultingbreakdown products of the polymers comprising a medical device may bemore “friendly,” or less irritating or immunogenic, to the host, suchas, for example, the vascular wall. When the polymer composition isdesigned to elicit slow breakdown kinetics, tissue overload or otherinflammatory responses at the site of implantation may be avoided.

Further disclosed herein is a method for making a bioabsorbable medicaldevice of the present invention comprising: blending a crystallizablecomposition comprising a base polymer of poly L-lactide or polyD-lactide linked with modifying copolymers comprising poly L(orD)-lactide-co-Tri-methylene-carbonate or poly L(orD)-lactide-co-ε-caprolactone in the form of block copolymers or asblocky random copolymers wherein the lactide chain length issufficiently long enough to allow cross-moiety crystallization; moldingthe polymer composition to structurally configure said implant; andcutting the implant to form desired patterns.

Another method for fabricating a medical device of the presentapplication comprises: preparing a biodegradable polymeric structure;designing said polymeric structure to be configured to allow forimplantation into a patient; cutting said structure into patternsconfigured to permit traversing of the device through openings and toallow for crimping of the device (as described in co-pending patentapplication Ser. No. 11/781,225, filed concurrent herewith). Embodimentsutilizing secondary meandering struts which are expanded to thecrystallized hoop form (as described in co-pending patent applicationSer. No. 11/781,225, filed concurrent herewith) are particularly usefulin securing the scaffold implant in the organ space as the crystallinemoiety is less rapidly degraded and bioabsorbed and thereforeadvantageously capable of maintaining position and integrity of thescaffold, thus preventing premature collapse and dangerous bulk break-upof the scaffold.

As is well understood in the art, the polymeric scaffolds of the abovedescribed embodiments may lack contrast to be detected by the currentlyavailable detection devices such as x-ray monitors. Therefore, thecontrast detection enhancement of tissue implants by electron-dense orx-ray retractile markers is advantageous. Such markers can be found inbiodegradable spot depots filled with radiopaque compositions preparedfrom materials known to refract x-radiation so as to become visible inphotographic images (FIGS. 3-7). Suitable materials include withoutlimit, 10-90% of radiopaque compounds or microparticles which can beembedded in biodegradable moieties, particularly in the form of pastelike compositions deposited in a plurality of cup shaped receptacleslocated in preformed polymeric scaffold strut elements.

The radiopaque compounds can be selected from x-radiation dense orrefractile compounds such as metal particles or salts. Suitable markermetals may include iron, gold, colloidal silver, zinc, magnesium, eitherin pure form or as organic compounds. Other radiopaque material istantalum, tungsten, platinum/iridium, or platinum. The radiopaque markermay be constituted with a binding agent of one or more aforementionedbiodegradable polymer, such as PLLA, PDLA, PLGA, PEG, etc. To achieveproper blend of marker material a solvent system is includes two or moreacetone, toluene, methylbenzene, DMSO, etc. In addition, the markerdepot can be utilized for an anti-inflammatory drug selected fromfamilies such as PPAR agonists, steroids, mTOR inhibitors, Calcineurininhibitors, etc.

In one embodiment comprising a radioopaque marker, iron containingcompounds or iron particles encapsulated in a PLA polymer matrix toproduce a pasty substance which can be injected or otherwise depositedin the suitably hollow receptacle contained in the polymeric strutelement. Such cup-like receptacles are dimensioned to within the widthof a scaffold strut element. Heavy metal and heavy earth elements areuseful in variety of compounds such as ferrous salts, organic iodinesubstances, bismuth or barium salts, etc. Further embodiments that maybe utilized may encompass natural encapsulated iron particles such asferritin that may be further cross-linked by cross-linking agents.Furthermore, ferritin gel can be constituted by cross-linking with lowconcentrations (0.1-2%) of glutaraldehyde.

The radioopaque marker may be applied and held in association with thepolymer in a number of manners. For example, the fluid or paste mixtureof the marker may be filled in a syringe and slowly injected into apreformed cavity or cup-like depression in a biodegradable stent strutthrough as needle tip. The solvents contained in the fluid mixture canbond the marker material to the cavity walls. The stent containingradiopaque marker dots can be dried under heat/vacuo. Afterimplantation, the biodegradable binding agent can breakdown to simplemolecules which are absorb/discharged by the body. Thus the radiopaquematerial will become dispersed in a region near where first implanted.

While the invention has been particularly shown and described withreference to particular embodiments, it will be appreciated thatvariations of the above-disclosed and other features and functions, oralternatives thereof, may be desirably combined into many otherdifferent systems or applications. Also that various presentlyunforeseen or unanticipated alternatives, modifications, variations orimprovements therein may be subsequently made by those skilled in theart which are also intended to be encompassed by the following claims.

Now turning to the remaining figures:

FIG. 1 depicts change in modulus with recrystallization of LPLA/LPLA/TMCnon-racemate blend versus a DPLA/LPA/TMC with only cross moiety racemateand a DPLA/LPLA/LPLA-TMC with additional racemate formation;

FIG. 2A and FIG. 2B depict DSC curves of polymer with racemate andwithout racemate formation, respectively: as illustrated racemate meltis shown to be significantly different in profile for the +racemate vs.the −racemate.

FIGS. 3A-3G illustrate an embodiment method of radiopaque depot markingof a stent medical device: as seen in (a)-(d), radiopaque material maybe extruded into a cavity housed in the structure (g). As seen incut-off views (e) and (f), such cavity may be a through-hole.

FIGS. 4A-4C illustrates different stent patterns of a scaffold withradiopague markers. As illustrated, the radiopaque markers can be placedat different locations on the stent patterns, while still allowingdetection using radiopaque detection means.

FIG. 5A and FIG. 5B illustrate a planar view of a stent material withradiopaque markers. As illustrated in FIGS. 5A and 5B, the radiopaquemarkers can be aligned in the structure to allow for easieridentification upon imaging or use of other detection methods.

FIG. 6 shows an overview perspective of an actual stent with anembodiment radiopaque marker pattern, each located at a connectionjunction of the meandering strut.

FIG. 7 shows a close-up view of a portion of the radiopaque marked stentof FIG. 6.

FIG. 8 shows in perspective view a stent embodiment of the presentinvention deployed on a balloon catheter.

FIG. 9 depicts a fully expanded bioabsorbable scaffold stent comprisingring structuring showing fully crystallized holding rings or hoops.

FIG. 10A and FIG. 10B illustrates DSC flow curves demonstrating singleTg and 10B shows a DSC flow curve showing double Tg.

Taking reference to FIG. 10A, polymer samples were analyzed for thermaltransition temperatures using TA instrument Q10 DSC. The samples were(A) Poly (L-co-DL-lactide) 70:30 copolymer, (B) Poly (L-lactide/PolyL-lactide-co-ε-caprolactone), and (C) Poly (L-lactide/PolyL-lactide-co-TMC). The polymers gave broad transition peaks at Tg's of30° C. and 50° C., which were only present on the original run.Transition temperatures and curves of the later runs are given in thetable below.

TABLE Transition Polymer Temperature (C.) PLDL 70/30 66 LPLA/PCL Hybrid64 LPLA/TMC 61

Taking reference to FIG. 10B, other polymer samples (LPLA/TMC hybrid)were analyzed via DSC showing a double Tg.

What is claimed is:
 1. A bioabsorbable stem comprising a crystallizedpolymer composition, the polymer composition comprising: poly(L-lactide-co-Tri-methylene-carbonate) or poly(D-lactide-co-tri-methylene-carbonate) or poly(L-lactide-co-ε-caprolactone) or poly (D lactide-co-ε-caprolactone), inthe form of block copolymers or blocky random copolymers.
 2. The stem ofclaim 1, wherein the polymer composition comprises poly(L-lactide-co-ε-caprolactone) or poly (D-lactide-co-ε-caprolactone). 3.The stent of claim 1, wherein the polymer composition comprises poly(L-lactide-co-ε-caprolactone).
 4. The stent of claim 1, furthercomprising poly (L-lactide) moiety, and/or a poly (D-lactide) moiety,and/or poly L-lactide-co-Peg moiety, and/or poly D-lactide-co-PEGmoiety.
 5. The stent of claim 4, wherein the polymer comprisespoly(L-lactide) and/or poly(D-lactide).
 6. The stem of claim 3, furthercomprising a poly (L-lactide) moiety, and/or a poly (D-lactide) moiety,and or poly L-lactide-co-PEG moiety, and/or poly D-lactide-co-PEGmoiety.
 7. The stem of claim 6, wherein the polymer comprisespoly(L-lactide).
 8. The stem of claim 7, wherein the polymer compositionis further crystallized upon expansion of the stent.
 9. The stem ofclaim 7, wherein the stem is balloon-expandable.
 10. The stent of claim7, wherein the stem comprises a hoop structure.
 11. The stem of claim 7,further comprising at least one radiopaque marker.
 12. The stent ofclaim 7, further including at least one pharmaceutical agent.
 13. Thestem of claim 7, further including a barrier layer which contains atleast one pharmaceutical agent.
 14. The stent of claim 8, wherein thepolymer composition is crystallized in scaffold struts upon orthogonalstrain deployment.
 15. A bioabsorbable scaffold comprising acrystallized polymer composition, the polymer composition comprising:poly (L-lactide-co-Tri-methylene-carbonate) or poly(D-lactide-co-tri-methylene-carbonate) or poly(L-lactide-co-ε-caprolactone) or poly (D-lactide-co-ε-caprolactone), inthe form of block copolymers or blocky random copolymers.